Most of an oral glucose load is taken up by muscle in man. We have previously demonstrated the importance of carbohydrate storage in distinguishing between individuals with low and high insulin-mediated glucose disposal. Reduced insulin-mediated glucose storage is associated with a reduced muscle glycogen synthase activity in man. In our effort to further clarify the importance of the regulation of muscle glycogen synthase to the regulation of insulin-mediated glucose storage, we have observed the following: insulin activation of glucose storage and glycogen synthase have similar ED50 values. Subjects with low insulin-mediated glucose disposal rates have dose-response curves for both glycogen synthase and glucose storage which are shifted to the right (lower sensitivity) and have reduced capacity. Diabetic subjects have reduced fasting muscle glycogen concentrations and reduced total glycogen synthase activity. Non-diabetic subjects show a negative correlation between fasting plasma glucose and their muscle glycogen content and their total glycogen synthase activity (active plus inactive forms). These results suggest that glycogen synthase activity is closely associated with the process of glucose disposal and that alterations in the regulation of the enzyme coincide with the altered glucose storage observed in subjects with low insulin-mediated glucose storage rates. The elevated G-6-P content in muscle from subjects with low insulin-mediated glucose disposal rates indicates that the most significant reduction in their glucose metabolism occurs post-G-6-P. In addition, preliminary results suggest that a large fraction of stored glucose ends up as muscle glycogen. Taken together, these results suggest that abnormal insulin regulation of glycogen synthase may account for a large part of the reduced insulin-mediated glucose disposal.